Neurotransmitters act through specific receptors and are responsible for regulating the conductance of ions (e.g., K.sup.+, Na.sup.+, Cl.sup.-) across semi-permeable neuronal cell membranes. The active concentration of charged ions within a cell results in the establishment of an electrical potential across the membrane of the cell. A resting neuronal cell, for example, has a membrane potential of about -80 mv, the interior being negative with respect to the exterior of the cell. Neurotransmitters are stored in presynaptic vesicles and are released under the influence of neuronal action potentials. When released into the synaptic cleft, an excitatory chemical will generally cause membrane depolarization.
L-glutamate is thought to be the major excitatory neurotransmitter in the central nervous system. Two major pharmacological classes of glutamate-mediated ion channels have been identified. N-methyl-D-aspartate (NMDA) receptors respond preferentially to the synthetic analog of aspartate, N-methyl-D-aspartate, whereas non-NMDA receptors respond preferentially to kainate and .alpha.-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA). Glutamate-induced NMDA receptors have attracted particular attention by virtue of their proposed role in long-term potentiation, learning, hypoxic neuronal damage, and epilepsy.
Although steroid effects mediated by genomic steroid response elements have been studied extensively, it is now evident that many steroids also have direct neuromodulatory effects on a variety of neurotransmitter receptors. Moreover, there is evidence for the local synthesis of certain steroids (termed "neurosteroids") in the brain. In particular, the neurosteroid pregnenolone sulfate (FIG. 1) has been proposed as an endogenous negative modulator of the GABA receptor in the brain. It has been previously shown that pregnenolone sulfate is a negative modulator of the glycine receptor.